During T cell development, thymocytes that are able to recognize self MHC are signaled to mature (positive selection), whereas those capable of self reactivity die (negative selection). Many of our studies deal with these selection processes that result from interactions that occur between T cell receptors (TCR) on developing T cells with MHC on antigen presenting cells in the thymic microenvironment. Experiments have been performed in order to determine how and when T cells commit to the CD4 and CD8 lineages. Since CD4 and CD8 T cells arise from a common CD4+8+ precursor, coreceptor (CD4 or 8) expression in mature T cells appears to be linked to MHC class recognition by TCR. Experiments involving TCR and CD8 transgenic mice were used to test whether lineage commitment occurs by a stochastic process or is directed by the class of MHC that the TCR and coreceptor coengage during the course of thymic selection. Our studies show that at least some T cells can be selected on more than one MHC and imply that positive selection is a multi-step process involving a stochastic event that randomly modulates one of the coreceptors on CD4+8+ immature T cells. In other studies, we find that at least a few T cells can be rescued with an inappropriate coreceptor (inappropriate for the MHC specificity of the TCR on the same T cell) when the appropriate coreceptor is expressed as a transgene. Most of the results suggest that there is a stochastic component regulating coreceptor expression in T cell development; however, the data do not as yet establish whether this is a major pathway for the bulk of T cells and/or whether the stochastic process actually mediates lineage commitment. Collaborative studies with W. Leonard of NHLBI have established that IL-2Rgamma is expressed in the thymus. Studies are under way to explain how mutation of this gene could account for the failure to generate mature T cells that is observed in human severe combined immunodeficiency disease (SCID). Collaborative studies are in progress with F. Alt using terminal deoxynucleotidyl transferase (TdT)-deficient mice in order to establish whether T cells that lack N regions in their TCR variable regions undergo normal thymic development and selection and/or mediate normal antigen recognition.